Promiscuous gene expression

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Promiscuous gene expression (PGE), formerly referred to as ectopic expression, is a process specific to the thymus that plays a pivotal role in the establishment of central tolerance. This phenomenon enables generation of self-antigens, so called tissue-restricted antigens (TRAs), which are in the body expressed only by one or few specific tissues (antigens rank among TRAs if they are expressed by less than five tissues from the sixty tested [1] ). These antigens are represented for example by insulin from the pancreas or defensins from the gastrointestinal tract. [2] Antigen-presenting cells (APCs) of the thymus, namely medullary thymic epithelial cells (mTECs), dendritic cells (DCs) and B cells are capable to present peptides derived from TRAs to developing T cells (thymus is the major origin of T cell development [3] ) and hereby test, whether their T cell receptors (TCRs) engage self entities and therefore their occurrence in the body can potentially lead to the development of autoimmune disease. In that case, thymic APCs either induce apoptosis in these autoreactive T cells (negative selection) or they deviate them to become T regulatory cells (Treg selection), which suppress self-reactive T cells in the body that escaped negative selection in the thymus. [4] Thus, PGE is crucial for tissues protection against autoimmunity.

Contents

Characteristics of PGE in distinct cell types

The usual level of gene expression in the peripheral tissues (e.g. spleen, kidney, liver etc.) reaches about 60% of the mouse coding genome. Some peripheral tissues, including lungs, brain and testis, reveal the repertoire of expressed genes about 10% broader. Importantly, PGE in the thymus, which is mediated by unique subset of epithelial cells called mTECs, triggers expression of vast majority of the genes from the whole genome (~85%). Such a broad repertoire of expressed genes wasn't shown in any other tissue of the body. [5]

mTECs

The process of PGE in the thymus was discovered in late 80's [6] however, it took a decade to find that the cell subset that mediates PGE and therefore provides a "library" of TRAs are mTECs. [7] These cells were shown to uniquely express a protein called autoimmune regulator (Aire), which drives the expression of approximately 40% TRAs, referred to as Aire-dependent, and is so far the only well characterized driver of PGE. [8] Defects in the expression of Aire lead to multiorgan autoimmunity in mice and cause a severe autoimmune syndrome called APECED in human. [9] [10] Because Aire is not the exclusive PGE regulator, more than half of TRAs are Aire-independent and it isn't still known how their PGE is orchestrated. [11]

mTECs are very heterogenous population and at least should be subdivided to MHCII low expressing subset (mTECsLO) and MHCII high expressing subset (mTECsHI) which is considered to be mature. [12] Aire is expressed only by 30% from the latter. [5]

PGE was found to act in a stochastic manner, which means that each mTEC expresses distinct set of Aire-dependent and Aire-independent TRAs. [13] Despite its stochasticity, TRAs are co-expressed in clusters which however, rather mirror their co-localization on chromosomes than co-expression patterns from particular tissues. Even though TRAs involved in each cluster were found to be consistent, the PGE of whole cluster is transient and changes during mTEC development. [14] Moreover, these clusters are highly variable between individuals. [15] PGE is distinct from the expression of TRAs in the peripheral tissues also by its monoalelic or bialelic course. [16] On the other hand, the level of TRA expression and numbers of alternative-splicing protein variants in the thymus correspond to the peripheral tissues. [17] [5]

PGE is highly conserved between mice and human. [18]

B cells

Although thymic B cells were shown to induce either negative selection or Treg selection, their importance for the establishment of central tolerance remains elusive. [19] [20] It is assumed however, that B cells in the thymus are licensed by CD40-CD40L interaction with autoreactive T cells to activate the expression of Aire and upregulate levels of MHCII and CD80. Moreover, Aire drives the PGE of Aire-dependent TRAs in B cells and because their repertoire is non-overlapping with that of mTECs it should broaden the scope of peripheral antigens displayed in the thymus. [21]

PGE in the periphery

Except the thymus, Aire is expressed also in the periphery, namely in the secondary lymphoid organs. However, the search for particular Aire-expressing cell type still continues due to conflicting results. [22] [23] What seems to be clear is that these cells express Aire-dependent TRAs, that are distinct from those in mTECs. [22] In line with their high expression of MHCII and very limited expression of costimulatory molecules, these cells were shown to establish tolerance by inactivation of autoreactive T cells rather than inducing apoptosis in them. [23]

Master-regulators of PGE

Aire and its partners

Aire is not classical transcription factor, because instead of recognition of specific consensus sequences, Aire seeks after genes marked by specific histone marks, such as the absence of H3K4me3 and presence of H3K27me3, which indicate transcriptionally inactive chromatin. [24] [25] [26] This type of gene recognition logically explains the high numbers of genes whose expression is affected by Aire. There is available also alternative explanation, that Aire recognizes silenced chromatin thanks to interaction with molecular complex ATF7ip- MBD1 which binds methylated CpG di-nucleotides. [27]

After the recognition of Aire dependent genes, Aire recruits topoisomerase II to perform double-strand DNA breaks at their transcriptional start sites (TSSs). [28] These brakes attract DNA PK and other DNA damage response proteins which relax the surrounding chromatin and repair the breaks. [29] [30] Subsequently, Aire recruits elongation complex p-TEFb to the TSSs, [31] which releases stalled RNA II polymerases and therefore activates transcription (PGE) of Aire-dependent genes. [32] Interaction between Aire and p-TEFb is enabled by another partner molecule Brd4, which stabilizes this molecular complex. [33]

Altogether, Aire requires around fifty partner molecules to properly activate PGE. [30] Among these molecules further rank acetylase Creb-binding protein (CBP), which enhances stability of Aire, however dampens its transactivation properties and deacetylase Sirtuin 1 (Sirt1), which is essential for activation of PGE of Aire-dependent TRAs. [34] [35] Worth mentioning is also Hipk2, which phosphorylates Aire and CBP however, its absence affects mostly PGE of Aire-independent genes, suggesting that this kinase might cooperate with other unknown transcriptional regulator. [36]

Recently, molecular complexes of Aire and its partners were shown to localize to specific parts of chromatin called super-enhancers. [37]

By contrast, little is known about transcription of Aire itself. Nevertheless, several studies suggest that major role in triggering of Aire expression plays NF-κB signaling pathway, [38] [39] similarly as in the development of mTECs. [40] Aire expression and PGE of Aire-dependent TRAs is also affected by sex hormones. Androgens enhance these processes, whereas impact by estrogens is completely opposite and results in less efficient PGE. [41] [42]

Fezf2

Fezf2 (forebrain embryonic zinc-finger-like protein 2) was recently discovered as the second regulator of PGE. [43] Even though little is known about its operation in the thymus, Fezf2, in marked contrast with Aire, plays role in different physiological processes than central tolerance, e.g. development of the brain, and acts as a classical transcription factor. In the thymus however, Fezf2 is expressed by nearly 80% of mTECs and not other cells. The repertoire of TRAs involved in Fezf2-driven PGE is nonoverlapping with that of Aire and comprises genes previously defined as Aire-independent, e.g. Fabp9 (TRA of testis). This fact is also bolstered by different manifestations of autoimmunity in Fezf2 knockout mouse, in comparison with Aire KO mouse. [44]

The expression of Fezf2 was found to be independent on Aire however, was found to be triggered also by the receptor of NF-κB signaling pathway, namely by LtβR. [43]

The expression of Aire and Fezf2 was found to be upregulated after mTEC adhesion to developing T cells which points to the fact that functional PGE requires direct contact with T cells. [45]

Related Research Articles

<span class="mw-page-title-main">Thymus</span> Endocrine gland

The thymus is a specialized primary lymphoid organ of the immune system. Within the thymus, thymus cell lymphocytes or T cells mature. T cells are critical to the adaptive immune system, where the body adapts to specific foreign invaders. The thymus is located in the upper front part of the chest, in the anterior superior mediastinum, behind the sternum, and in front of the heart. It is made up of two lobes, each consisting of a central medulla and an outer cortex, surrounded by a capsule.

<span class="mw-page-title-main">T cell</span> White blood cells of the immune system

T cells are one of the important types of white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell surface.

<span class="mw-page-title-main">FOXP3</span> Immune response protein

FOXP3, also known as scurfin, is a protein involved in immune system responses. A member of the FOX protein family, FOXP3 appears to function as a master regulator of the regulatory pathway in the development and function of regulatory T cells. Regulatory T cells generally turn the immune response down. In cancer, an excess of regulatory T cell activity can prevent the immune system from destroying cancer cells. In autoimmune disease, a deficiency of regulatory T cell activity can allow other autoimmune cells to attack the body's own tissues.

Cross-presentation is the ability of certain professional antigen-presenting cells (mostly dendritic cells) to take up, process and present extracellular antigens with MHC class I molecules to CD8 T cells (cytotoxic T cells). Cross-priming, the result of this process, describes the stimulation of naive cytotoxic CD8+ T cells into activated cytotoxic CD8+ T cells. This process is necessary for immunity against most tumors and against viruses that infect dendritic cells and sabotage their presentation of virus antigens. Cross presentation is also required for the induction of cytotoxic immunity by vaccination with protein antigens, for example, tumour vaccination.

In immunology, central tolerance is the process of eliminating any developing T or B lymphocytes that are autoreactive, i.e. reactive to the body itself. Through elimination of autoreactive lymphocytes, tolerance ensures that the immune system does not attack self peptides. Lymphocyte maturation occurs in primary lymphoid organs such as the bone marrow and the thymus. In mammals, B cells mature in the bone marrow and T cells mature in the thymus.

Immune tolerance, or immunological tolerance, or immunotolerance, is a state of unresponsiveness of the immune system to substances or tissues that would otherwise have the capacity to elicit an immune response in a given organism. It is induced by prior exposure to that specific antigen and contrasts with conventional immune-mediated elimination of foreign antigens. Tolerance is classified into central tolerance or peripheral tolerance depending on where the state is originally induced—in the thymus and bone marrow (central) or in other tissues and lymph nodes (peripheral). The mechanisms by which these forms of tolerance are established are distinct, but the resulting effect is similar.

A thymocyte is an immune cell present in the thymus, before it undergoes transformation into a T cell. Thymocytes are produced as stem cells in the bone marrow and reach the thymus via the blood.

<span class="mw-page-title-main">Hassall's corpuscles</span>

Hassall's corpuscles (or thymic corpuscles (bodies)) are structures found in the medulla of the human thymus, formed from eosinophilic type VI epithelial reticular cells arranged concentrically. These concentric corpuscles are composed of a central mass, consisting of one or more granular cells, and of a capsule formed of epithelioid cells. They vary in size with diameters from 20 to more than 100μm, and tend to grow larger with age. They can be spherical or ovoid and their epithelial cells contain keratohyalin and bundles of cytoplasmic fibres. Later studies indicate that Hassall's corpuscles differentiate from medullary thymic epithelial cells after they lose autoimmune regulator (AIRE) expression. This makes them an example of Thymic mimetic cells. They are named for Arthur Hill Hassall, who discovered them in 1846.

<span class="mw-page-title-main">Autoimmune regulator</span> Immune system protein

The autoimmune regulator (AIRE) is a protein that in humans is encoded by the AIRE gene. It is a 13kb gene on chromosome 21q22.3 that has 545 amino acids. AIRE is a transcription factor expressed in the medulla of the thymus. It is part of the mechanism which eliminates self-reactive T cells that would cause autoimmune disease. It exposes T cells to normal, healthy proteins from all parts of the body, and T cells that react to those proteins are destroyed.

Self-protein refers to all proteins endogenously produced by DNA-level transcription and translation within an organism of interest. This does not include proteins synthesized due to viral infection, but may include those synthesized by commensal bacteria within the intestines. Proteins that are not created within the body of the organism of interest, but nevertheless enter through the bloodstream, a breach in the skin, or a mucous membrane, may be designated as “non-self” and subsequently targeted and attacked by the immune system. Tolerance to self-protein is crucial for overall wellbeing; when the body erroneously identifies self-proteins as “non-self”, the subsequent immune response against endogenous proteins may lead to the development of an autoimmune disease.

<span class="mw-page-title-main">XCR1</span> Protein-coding gene in the species Homo sapiens

The "C" sub-family of chemokine receptors contains only one member: XCR1, the receptor for XCL1 and XCL2.

In immunology, peripheral tolerance is the second branch of immunological tolerance, after central tolerance. It takes place in the immune periphery. Its main purpose is to ensure that self-reactive T and B cells which escaped central tolerance do not cause autoimmune disease. Peripheral tolerance prevents immune response to harmless food antigens and allergens, too.

<span class="mw-page-title-main">IKZF1</span> Protein-coding gene in the species Homo sapiens

DNA-binding protein Ikaros also known as Ikaros family zinc finger protein 1 is a protein that in humans is encoded by the IKZF1 gene.

In immunology, clonal deletion is the removal through apoptosis of B cells and T cells that have expressed receptors for self before developing into fully immunocompetent lymphocytes. This prevents recognition and destruction of self host cells, making it a type of negative selection or central tolerance. Central tolerance prevents B and T lymphocytes from reacting to self. Thus, clonal deletion can help protect individuals against autoimmunity. Clonal deletion is thought to be the most common type of negative selection. It is one method of immune tolerance.

<span class="mw-page-title-main">Medullary thymic epithelial cells</span>

Medullary thymic epithelial cells (mTECs) represent a unique stromal cell population of the thymus which plays an essential role in the establishment of central tolerance. Therefore, mTECs rank among cells relevant for the development of functional mammal immune system.

Antigen transfer in the thymus is the transmission of self-antigens between thymic antigen-presenting cells which contributes to the establishment of T cell central tolerance.

<span class="mw-page-title-main">Cortical thymic epithelial cells</span>

Cortical thymic epithelial cells (cTECs) form unique parenchyma cell population of the thymus which critically contribute to the development of T cells.

Thymic epithelial cells (TECs) are specialized cells with high degree of anatomic, phenotypic and functional heterogeneity that are located in the outer layer (epithelium) of the thymic stroma. The thymus, as a primary lymphoid organ, mediates T cell development and maturation. The thymic microenvironment is established by TEC network filled with thymocytes in different developing stages. TECs and thymocytes are the most important components in the thymus, that are necessary for production of functionally competent T lymphocytes and self tolerance. Dysfunction of TECs causes several immunodeficiencies and autoimmune diseases.

Thymus stromal cells are subsets of specialized cells located in different areas of the thymus. They include all non-T-lineage cells, such as thymic epithelial cells (TECs), endothelial cells, mesenchymal cells, dendritic cells, and B lymphocytes, and provide signals essential for thymocyte development and the homeostasis of the thymic stroma.

Thymic mimetic cells are a heterogeneous population of cells located in the thymus that exhibit phenotypes of a wide variety of differentiated peripheral cells. They arise from medullary thymic epithelial cells (mTECs) and also function in negative selection of self-reactive T cells.

References

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  45. ↑ Passos, Geraldo A.; Giuliatti, Silvana; Bombonato-Prado, Karina F.; Lopes, Gabriel S.; Pezzi, Nicole; Cotrim-Sousa, Larissa; Felicio, Rafaela F.; Assis, Amanda F.; Speck-Hernandez, Cesar A. (2018). "Aire Disruption Influences the Medullary Thymic Epithelial Cell Transcriptome and Interaction With Thymocytes". Frontiers in Immunology. 9: 964. doi: 10.3389/fimmu.2018.00964 . ISSN   1664-3224. PMC   5949327 . PMID   29867946.
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